Intellectual disability
Gene: RALA

RALA (RAS like proto-oncogene A)
EnsemblGeneIds (GRCh38): ENSG00000006451
EnsemblGeneIds (GRCh37): ENSG00000006451
OMIM: 179550, Gene2Phenotype
RALA is in 3 panels

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: Gene status was changed to Green due to a expert review by Konstantinos Varvagiannis. Hiatt et al. (PMID: 30500825) report on 11 individuals (incl. a pair of monozygotic twins) from 10 unrelated families, most (10/11) with de novo mutations in RALA.

DD/ID was a prominent feature (the authors note that ID was specifically noted in 8 but could not be excluded in 3 further individuals who appear to be very young in the table).

Functional studies demonstrated reduction in GTPase activity (for all variants) and altered RALA effector binding (for most reduction - in the case of S157A, increase). Several lines of evidence are provided to show that alteration of the GTP/GDP-binding rather than a dosage effect is considered the likely mechanism.
Created: 29 May 2019, 9:12 a.m.

Created: 29 May 2019, 9:12 a.m.

Panel version: Imported from Intellectual disability update May 2019 panel version 0.94

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Hiatt et al. (doi.org/10.1371/journal.pgen.1007671) report on 11 individuals (incl. a pair of monozygotic twins) from 10 unrelated families, most (10/11) with de novo mutations in RALA.

DD/ID was a prominent feature (the authors note that ID was specifically noted in 8 but could not be excluded in 3 further individuals who appear to be very young in the table). Structural brain anomalies (9/11), seizures (6/11) and common facial features were also noted.

RALA belongs to the RAS superfamily of small GTPases.

5 different de novo missense variants and 1 in-frame deletion, all within a GTP/GDP binding region of RALA (although apart in the protein primary structure) were observed. 7 occurrences of missense variants concerned Val25 and Lys128 (V25M, V25L, K128R), one Asp130 (D130G) and a further one Ser157 (S157A). The in-frame deletion concerned Ala158.

Missense variants in corresponding positions of RAS proteins (HRAS/KRAS/NRAS) have been reported in RASopathies, while the authors observed some phenotypic overlap with the latter group of disorders (DD/ID, growth delay, macrocephaly, high forehead and position of ears).

Functional studies demonstrated reduction in GTPase activity (for all variants) and altered RALA effector binding (for most reduction - in the case of S157A, increase).

Several lines of evidence are provided to show that alteration of the GTP/GDP-binding rather than a dosage effect is considered the likely mechanism. RALA is depleted in missense mutations in its GTP/GDP binding domain.

For these reasons and others (segregation studies not possible, variant observed 2x in Bravo database, phenotypic differences compared to the rest of the cohort, ROH suggesting parental consanguinity in the specific individual) the single nonsense variant (R176X) reported in the study is considered a VUS by the authors.

As a result, this gene can be considered for inclusion in this panel as green.
Sources: Literature
Created: 1 Dec 2018, 11:33 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Created: 1 Dec 2018, 11:33 a.m.

Panel version: 2.562

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Expert Review
Expert Review Green
Expert Review

Phenotypes

Global developmental delay
Seizures
Abnormality of nervous system morphology
Global developmental delay, Intellectual disability, Seizures, Abnormality of nervous system morphology
Intellectual disability

OMIM

179550

Clinvar variants

Variants in RALA

Penetrance

unknown

Publications

30500825

Mode of Pathogenicity

Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Panels with this gene

History Filter Activity

25 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to RALA. Source Expert Review was added to RALA. Added phenotypes Global developmental delay, Intellectual disability, Seizures, Abnormality of nervous system morphology for gene: RALA Publications for gene RALA were changed from to 30500825 Rating Changed from No List (delete) to Green List (high evidence)

1 Dec 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set Phenotypes, Set penetrance, Set mode of pathogenicity

Konstantinos Varvagiannis (Other)

gene: RALA was added gene: RALA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RALA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: RALA were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology Penetrance for gene: RALA were set to unknown Mode of pathogenicity for gene: RALA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: RALA was set to GREEN

Intellectual disability Gene: RALA